Management Of Gout

1 Definition

Inflammatory arthritis triggered by crystallization of monosodium urate within the joints when uric acid, the end-product of purine metabolism, exceeds its limit of solubility in body fluids.

Hyperuricaemia is NOT gout, rather it is a risk factor for gout.
(Limit of urate solubility at physiologic temperature and pH is 6.8mg/dL, approx 404 umol/L)

Note: Gout Classification Criteria by American College of Rheumatology/ European League Against Rheumatism (2015) can be assessed online at: ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 10, October 2015, pp 2557–2568.

2 Epidemiology

• Global prevalence – 0.08%
• 1-2% of adult men in western countries
• Ratio of male to female: 3 or 4 to 1
• Peak onset of gout in males 40-50 years and in female is after 60 years

3 Pathophysiology

• Factors for Increased Urate Level
  • Overproduction
  • Under-excretion – believed to be the major factor
  • Possibly – Increased Intake
• The crystals commonly deposit in tissues with limited blood flow – tendons, cartilage, ligaments, bursa, skin in areas that are cooler or around distal joints.
• Tophi are large urate deposits in skin

4 Clinical Features
Stages of Development

• Asymptomatic hyperuricemia
• Acute gouty arthritis
• Inter-critical (interval) gout
• Chronic tophaceous gout
  Acute and chronic gout will be discussed further.

4.1 Acute Gout
History

• Abrupt onset, usually at night, severe excruciating pain/ redness
• Usually at the extremity or distal joints
• Usually mono-arthritis (80%)
  
• Can be associated with triggering factors such as surgery, infection

Examination

• Swollen, red, tender joint, inflamed adjacent area

4.2 Chronic Gout (+/- Tophi)

• Recurrent joint pain / inflammation in a polyarticular pattern
• Tophi formation / Joint destruction
• Can mimic inflammatory arthritis eg RA

Fig 2: Images of chronic tophaceous gout minicking RA

Fig 3: Images of disabling chronic tophaceous gout

5 Investigations

• Full blood count
  • Neutrophil leucocytosis can be seen in acute attack, should be differentiated from septic arthritis
• Serum uric acid level
  • Usually raised, can be normal or even low in acute attack

• Serum creatinine
  • To exclude CKD that can lead to hyperuricemia and gout
• Investigations for detection of associated cardiovascular risk factors
  • Lipid profile
  • Blood sugar
  • ECG
• X ray of the affected joint – cortical break in bone suggestive of gout (overhanging edge with sclerotic margin), can be normal in acute gout

Fig 4: Images of an x ray on hands of severe chronic tophaceous gout

• Ultrasound examination of the affected joint – (if resources permit) – hyperechoic band over anechoic cartilage (double contour sign), presence of tophi, joint effusions and erosions
• Polarized light microscopy of joint aspirate – (if resources permit) – needle shaped, negatively birefringent gout crystals

6 Treatment

6.1 Acute Gout

• Aim: to suppress the inflammation

6.1.1 Pharmacological treatment: –

• Non-steroidal anti-inflammatory drugs (NSAIDS)
  • Start early, may need to keep until 48 hours after the resolution of attack
  • Beware of contraindications Eg Peptic ulcer disease, renal impairment
  • Use proton pump inhibitors if necessary
  • Any agent can be used
  • Give full dose
• Colchicine
  • For acute gout and prophylaxis of flares
  • Be cautious in renal, hepatic and bone marrow disease
  • 1.2 or 1 mg stat followed by 0.6 or 0.5 mg 1 hour and 12 hours later and then twice a day (or once a day) until acute attack resolved
  • Dose reduction in renal failure:
    • According to Creatinine clearance (Cr. Cl)
    • 30 – 50 ml/min: 0.5 mg maximum daily
    • 10 – 30ml/min: 0.5 mg 2 – 3 X per week.
    • To avoid if CrCl < 10 ml/min
  • Drug interactions – statins, fibrates, clarithromycin, erythromycin, ketoconazole, itraconazole, verapamil, diltiazam, protease inhibitors, cyclosporine,
• Corticosteroids
  • Indicated if contraindication to
    • NSAIDS: Peptic Ulcer Disease, renal, liver and cardiac failure
    • Colchicine: Renal (CCT < 50 ml/min), liver dysfunction
    • Not effective with NSAIDS
  • Steroids can be used in the form of
    • Intra-articular – limited to one or two joints, amenable to aspiration and in the absence of joint sepsis – refer to specialist
    • Systemic (Prednisolone 15 – 30 mg or equivalent dose of injectable form / day for 5 days)
    • IM ACTH 1mg
• IL-1 inhibitors (Canakimumab, Rilonacept, Anakinra) – currently unavailable in Myanmar

6.1.2 Supportive management

• Rest the joint / ice the joint

6.2 Chronic Gout – Urate Lowering Therapy (ULT)

6.2.1 General Information

• Should be initiated concurrently with acute gout treatment of 2-4 weeks after flare resolution or simultaneously; consider patient factors
• Target serum uric acid level – 6mg/dl (350μmol /L), 5 mg/dl (300μmol /L) in association with CKD, uric acid stone
• Indications
  • Two or more acute attacks in a year
  • Single attack with
    • Tophi in soft tissues or subchondral bone
    • Clinical or radiographic signs of chronic gouty arthritis
    • Renal insufficiency
    • Nephrolithiasis
    • Very high serum uric acid at presentation (>9mg/dL)
• Lifelong treatment

6.2.2 Medications

• 3 main classes

6.2.2.1 Xanthine Oxidase Inhibitors – Allopurinol, Febuxostat

• Allopurinol –
  • First Line
  • Renally excreted, usually safe
  • S/E – GI,rash, sarcoid like reaction, Allopurinol Hypersensitivity Syndrome (AHS)
  • Drug interaction – esp. with 6 Mercaptopurine, Azathioprine, warfarin, theophylline.
  • Dose increase from 100 mg to 800 mg/day (usually 300mg/day)
  • Dose reduction in renal impairment
  • To increase allopurinol slowly – every 2-4 weeks, monitor for adverse effects.
• Febuxostat
  • Non-purine analog
  • Metabolized in the liver
  • Dose: 40mg -120mg
  • Contraindicated for use with Azathioprine, Mercaptopurine, Theophylline
  • No cross reactivity with Allopurinol – used in Allopurinol hypersensitive patients (with caution)

6.2.2.2 Uricosuric agents – Probenecid, Sulphipyrazone, Benzbomarone,

• Probenecid (500 mg – 2g/ day in 2 divided dose)
• Sulphinpyrazone (50 mg BD to 100 – 200 mg 3 – 4x per day)
• Benzbromarone (50 – 200 mg/day) – contraindicated in liver disease – fatal hepatitis
• All are relatively ineffective compared to xanthine oxidase inhibitors.
• Not used in:
  • renal calculi
  • Renal insufficiency (24 hrs urinary CrCl < 50 ml/min) except Benzbromarone (can be use when 24 hour urinary Cr Cl > 20 ml/min)
  • Combination therapies with xanthine oxidase inhibiors

6.2.2.3 Urate oxidase –
Uricase –Pegloticase – currently unavailable in Myanmar

6.2.3 Changing ULT – to consider when

• High serum uric concentrations (>6 mg/dl) despite maximum or maximum-tolerated dose
• Continued frequent gout flares (>2 flares/year)
• Non-resolving subcutaneous tophi.

6.2.4 Prophylaxis for acute attacks when initiating urate lowering therapy

• Acute fall in serum uric acid can precipitate gouty flare
• Reduces rate of recurrent attacks whether or not the uric acid is normal.
• Duration – 3 – 6 months since the start of urate lowering therapy
• Longer duration if large / multiple tophi
• Medications
  • Low dose colchicine 500 – 1000 mcg /day
  • Low dose NSAIDs
  • Low dose steroid
  • Choice – depends on patient factors

Fig 5: Targets for intervention in the treatment and prophylaxis of gout

7 Lifestyle and Adjunctive Therapies

• Obesity
  • Risk of gout significantly higher in men with BMI >25.
  • Mean weight loss of 5 kg resulted in a mean SU lowering of 1.1 mg/ dl
• Alcohol abuse
  • Drinking 2 or more cans of beers per day increase risk of gout by 2.5X
  • A unit of beer raised SU concentrations by 0.16 mg/dl.
• Low purine diet
  • Strict dieting can only lower serum uric acid by at most 120 mol/L (2 mg/dl)
  • Moderation in dietary purine consumption is indicated in those who habitually eat large amount of purine-containing food – red meat, seafood, organ meat
  • Plant based foods – no significant hyperuricemia (myths – to avoid plant-based foods – a hand-span above and below the ground, vegetables rich in seeds such as tomato. There is no evidence on worsening the hyperuricemia by ingesting plant-based foods)
• Fructose – Ingestion of 1 gm of fructose/kg of body weight increases SU concentration by 1–2 mg/dl within 2 hours of ingestion; avoid soft drinks

8 Comorbid Conditions

• Hypertension
  • Diuretics – consider changing to other drugs
  • losartan – has uricosuric effect – to consider to use it
• Hyperlipidaemia
  • Fenofibrate has uricosuric effect – but not recommend switching from current treatment
• Low dose aspirin – can continue if there are indications, even though it can lead to hyperuricemia

9 When to refer to Physician/ Rheumatologist

• Unable to achieve the target uric acid level with optimal dosing
• Severe comorbidities
• Frequent gout flares despite regular treatment
• Severe complications from drug treatment

References

• 2020 American College of Rheumatology Guideline for the Management of Gout; Arthritis Care & Research Vol. 0, No. 0, June 2020, pp 1–17
  DOI 10.1002/acr.24180
• The British Society for Rheumatology Guideline for the Management of Gout, Rheumatology, Volume 56, Issue 7, July 2017, Pages e1–e20,
• Gout, Hyperuricemia, and Crystal- Associated Disease Network Consensus Statement Regarding Labels and Definitions for Disease Elements in Gout; Arthritis Care & Research Vol. 71, No. 3, March 2019, pp 427–434, DOI 10.1002/acr.23607
• UpToDate ;https://www.uptodate.com/contents/search

Author Information

Professor Cho Mar Lwin
Consultant Physician and Rheumatologist